Many nutritive, pharmaceutical and chemical materials are dispensed in convenient tablet or capsule form. In many cases, the amount of active ingredient required to accomplish a desired therapeutic, nutritive or chemical effect is very small. Inert diluents, fillers, binders, excipients and disintegrants, therefore, become very important in determining the practicality and convenience of making tablets or capsules to administer such active ingredients effectively.
There are a number of methods for making tablets. One of the most direct and efficient methods is by "direct compression tabletting." However, the direct compression tabletting apparatus requires a free-flowing powder material which completely and rapidly fills the mold prior to the application of compression. The free-flowing powder must also contain the desired amount of active ingredients to insure efficacy of the tablet for the intended purpose. This latter requirement is especially important in pharmaceutical tablets where too much active ingredient may be just as serious as too little.
The properties needed for a desirable carrier material include: flowability and correct particle size to facilitate accurate blending, and to facilitate correct and rapid loading of the direct compression tabletting apparatus; binding ability and bulk density to facilitate obtaining a tablet of sufficient hardness, substantially no friability, but which will readily disintegrate when ingested, or when put into use by otherwise subjecting it to moisture. Examples of such uses include aspirin tablets, including "Chewable" tablets, food additive tablets, plant fertilizer tablets, vitamin tablets, dry detergent tablets, animal feed medications and water treatment tablets. For certain specific purposes, such as efficacy tests, it may be desirable to administer "placebo" tablets containing no active ingredient, but otherwise indistinguishable from other tablets containing an active ingredient.
Some materials fill all the requirements for making a hard, non-friable tablet, but fail when the tablet is to be used. The carrier material in some cases does not aid in the disintegration of the tablet, and may actually prevent it. Fully gelatinized starch, which is considered 100% cold water soluble, behaves in the latter way. The outer surface of tablets made from fully gelatinized starch "gels" rapidly on contact with water. The tablet becomes "gummy" and never dissolves or disintegrates completely. Even a blend or mixture of fully gelatinized starch with granular starch does not dissolve effectively when tabletted. The completely cold water soluble, gelatinized portion of the blend tends to gel as indicated above, and it interferes with the disintegration of the remaining portion of the tablet.
Of the multitude of forms in which pharmaceutical products may be dispensed, the compressed tablet form is, by far, the most frequently employed today. Ease of packaging and handling, and, most important, accuracy of dosage in administration are among the advantages stemming from the use of medicament-containing tablets. For essentially the same reasons, the compressed tablet also plays an important role in other fields as a dispensing unit. Examples of non-pharmaceutical materials marketed in compressed tablet form include such diverse materials as laundry detergents, confections, artificial sweeteners, fish foods, plant growth regulators, pesticides, herbicides, and dyes. While the actual characteristics of various tablets differ depending on the particular nature and planned use of the several tablets, the generally more important characteristics fall into three areas of consideration.
Since most tablets are designed for use in accurately dispensing an active material into a fluid medium, an evaluation of the tablet includes a consideration of the tablet disintegration properties in the fluid medium. While some tablets, such as those designed for use as a throat lozenge, desirably are slowly disintegrative in the fluid medium in which they are placed for use, in most cases rapid disintegration of the tablet is desired. For example, a tablet embodying an ingestible analgesic, such as aspirin, should rapidly break down in the digestive fluid of the stomach to make the active ingredient promptly available to the organism.
The second and third important tablet characteristics, friability and hardness, are somewhat related in that as tablet hardness increases the friability of the tablet generally decreases. Excessive friability is undesirable, since dusting and crumbling of the tablet results in at least some diminution in active ingredient dosage, detracts from the tablet appearance and consumer appeal, and reduces the effectiveness of any tablet markings. Insufficiently hard tablets, in addition to exhibiting the effects of excessive friability, are prone to breakage and chipping, particularly in transport where they may be subjected to repeated mechanical shock.
Accordingly, for most purposes, and particularly for pharmaceutical application, a hard, non-friable tablet possessing acceptable disintegration characteristics is the goal of the tablet manufacturer. Other properties are, of course, important such as color stability and non-hygroscopicity, but the main criteria for a tabletting material is that it be freely flowable to load the tabletting machine, that it compress well to form a hard non-friable tablet, and that the resulting tablet disintegrate effectively when used.
Certain materials such as sodium chloride, paradichlorobenzene, hexamethylenetetramine, and certain medicaments are readily directly compressed alone in dry form into a firm, coherent mass in a tablet machine. However, the majority of active ingredients in order to be tabletted require a binding agent to be added. The tabletted formulations generally also contain additional ingredients, such as lubricants, disintegrants, fillers, glidants, colorants, and the like. The term "binding agent," "binder," and "filler" are self-explanatory. A disintegrant is an agent which is effective, when the tablet is placed in the proper fluid environment, to promote destruction of the tablet's physical integrity. A typical disintegrant employed in tabletting is granular starch, however, granular starch is not freely flowable and will not form a hard, non-friable tablet in direct compression tabletting apparatus. A given material may perform more than one of the single functions of binding, filling, and promoting disintegration. The goal of the tablet making is to find a material which performs as many of these functions as possible.
In general, three methods are known for the preparation of mixtures suitable to be employed in a tablet-making machine. In two of the methods commonly used for the preparation of tabletting machine feed material, the goal in each is the preparation of the feed material in the form of a free-flowing powder. One technique involves a dry, and the other a wet, method of granulation. Dry granulation is also referred to as "slugging" or "double compression." In accordance with the slugging technique, the initially prepared pulverulent admixture of active ingredient, filler, binder and the like is formed into large tablets or slugs by dry compression molding. These slugs are then milled to granules of predetermined size adapted to be used as the feed to the tablet-making machine. This method is expensive, requiring considerable equipment, labor and power. The technique, moreover, does not always provide suitable tablets.
The wet granulation technique involves adding a moistening agent such as water or ethylene glycol to the tabletting ingredient mixture to prepare a moistened mass, oven drying the wetted mass, and milling the dried mass into granules adapted to be used in the tabletting machine. The wet granulation method likewise is undesirably time-consuming and expensive. This method, moreover, has the limitation of not being useful when the tablet ingredients are incompatible to wetting or are heat-sensitive.
The third and simplest procedure employed in preparing tabletting formulations involves intimately and uniformly dry blending the ingredients employed, e.g., active ingredient, binder, filler, disintegrant, and lubricants, to provide a pulverulent powder mixture displaying the requisite flowability for adequate feeding to the direct compression tablet machine. Since in this method the granulation step is eliminated, the formulations are said to be "directly compressible" into tablets, and the tablet-forming operation is referred to as "direct-compression" tabletting.
Direct compression tabletting, by virtue of its simplicity is obviously preferred when it is possible to use. However, until now, the ingredient mixtures obtained by mere dry mixing generally did not exhibit adequate flowability and were not adapted to be fed directly to the tabletting machine to prepare tablets of uniform and acceptable properties.
Various attempts have been made to develop inexpensive, free-flowing powder carrier/binder materials for use in direct compression tabletting. U.S. Pats. Nos. 3,584,114, 3,725,556 and 3,873,694, each having a filing date junior to applicants' effective filing date, propose means for facilitating direct compression tabletting.
Cavalli et al. (U.S. Pat. No. 3,584,114) describe combining "poor flowing" powders (e.g., cornstarch) with melted waxy like edible materials such as stearic acid, Carbowax, glyceryl monostearate and the like. These patentees confirmed what applicants have already pointed out, that is, that a typical cornstarch is a poor flowing powder and requires improvement in its flowability to be useful in direct compression tabletting. The method disclosed by these patentees is complex, and requires additional ingredients.
Hanssen et al., U.S. Pat. No. 3,725,556 describe a method of direct compression tabletting which includes spray drying the inert ingredients and the active ingredients after inert gas foaming to avoid the conventional granulation step. The inert ingredients required by these patentees include finely divided silica or alumina, an inert filler which may be water-insoluble rice starch or cornstarch or an alkaline earth metal phosphate, and some amount of a water soluble binder which may be water soluble starch, or other named substances. Applicants' issued U.S. Pat. No. 3,622,677 was cited as prior art against the subject patent. It should be appreciated that applicants' free-flowing precompacted-starch powder provides all the functions in direct compression tabletting which are described for the more complex combination of ingredients disclosed by Hanssen et al.
More recently, U.S. Pat. No. 3,873,694 has described a direct compression tabletting composition which comprises a crystalline sugar admixed with a maltodextrin and sprayed with an aqueous solution of a maltodextrin. The patent reinforces applicants' statement regarding direct compression tabletting, and sets forth the ideal properties needed in a "direct compression vehicle." It is interesting to note that Example 9 of this patent describes an experiment to determine the effect of the precompacted-starch (STA-Rx 1500) of the subject invention on direct compressed tablets made using a granulated tabletting vehicle.
STA-Rx 1500 was used in an amount of 10% by weight to the weight of the total mixture. In those tablets having an active medicinal ingredient, STA-Rx 1500 displaced a portion of the granulated tabletting vehicle.
Table 10 of the subject patent clearly shows the improved disintegration effect obtained when STA-Rx 1500 was used. In all cases where it was used, there was a decrease in disintegration time by about one third of the original time for the same tablet without the subject precompacted-starch powder (STA-Rx 1500). Friability and tablet hardness were also considered good. This example in U.S. Pat. No. 3,873,694 shows that the subject precompacted-starch powder is compatible within the described dextrose/maltodextrin based tabletting materials, and can be used in such tablets to improve disintegration time. However, it is even more noteworthy that the subject precompacted-starch powder can completely replace the more costly and complex "sole binder disintegrant" described and claimed in this patent. The pregranulation step required for the dextrose/maltodextrin material described in the patent is not required in the examples set forth below.
The limited acceptance of preparing compressed tablets by direct compression has stemmed principally from the unavailability of suitable and inexpensive direct compression binding agents. Of those materials which do qualify by reason of their binding properties, moreover, few are characterized by satisfactory over-all properties. For example, one widely used binder material used in direct compression tabletting is spray-dried lactose. However, it is unacceptable in many uses because of its marked tendency to turn brown on aging. Because of such problems, most direct compression tabletting has required costly techniques such as the wet and dry granulation methods. As pointed out above, the search has continued to develop improved binder materials for use in direct compression tabletting. One major difficulty for which various solutions have been offered, is that many good binders and materials which tablet well do not dissolve properly when the tablet is used. They merely become glutinous globs in liquid, and do not release the active ingredients effectively.